PROJECT SUMMARY Photoreceptors are highly susceptible to disease states as they are some of the most metabolically active cells in the body. Massive photoreceptor death in diseases such as retinitis pigmentosa eventually leads to gross retinal disorganization and blindness, but the progression of this degeneration is not well understood. Earlier studies have been limited by using animal models in which photoreceptor death is uncontrolled in time and space. Current disease models are dysfunctional throughout development, and the disease-related changes observed are likely affected by developmental plasticity. In these models, the onset and duration of photoreceptor death are also sporadic, obscuring our understanding of the time-dependence of observed changes. Lesion models are not cell type specific, confounding the contribution of cone and rod populations to retinal degeneration. Studies have shown that massive photoreceptor death during development causes some post-synaptic bipolar cells to form new synapses with remaining photoreceptors and that complete photoreceptor loss drives the retinal circuit into spontaneously oscillatory activity. However, in human retinal disease, photoreceptor loss occurs in the adult circuit. It is not known whether retinal rewiring occurs when photoreceptors are lost in the adult retina or what impact partial photoreceptor death has on retinal function. The proposed work avoids these confounds by using a mouse line that affords control over the timing of cell death in a subpopulation of photoreceptors. Rapid death of cones expressing the short wavelength (S) opsin will be induced after retinal development is complete and cell-type specific analyses will be performed on the retina one to ten weeks after cone ablation. In Aim 1, we will identify the time course of structural changes in the dendritic and axonal terminals of genetically labeled type 6 cone bipolar cells after cone ablation. These cells receive input from S cones and provide the main input to the well-characterized alpha-type ganglion cells. These results will demonstrate the presence of adaptive structural plasticity in a specific adult retinal circuit. In Aim 2, we will investigate how cone ablation affects retinal processing by recording the electrophysiological activity of alpha-type ganglion cells, the most sensitive output cells of the retina, in response to light stimuli. These results will demonstrate the functional consequences of photoreceptor loss, including the retina's capacity to compensate for partial photoreceptor loss. Current therapies for vision loss include stem cell, viral, and prosthetic approaches, all of which rely on the remaining retinal circuitry. The results of the work proposed here will provide the understanding of the retinal circuit after photoreceptor death that will be required to optimize these therapies. By understanding how and when specific cell types react to photoreceptor loss, we will enhance our ability to provide treatment when it may be most effective. !